This invention relates to a new class of cephalosporins and their pharmaceutically acceptable salts and esters which are useful as long-acting antibiotics. This new class of cephalosporins are represented by formula I: ##STR3## wherein the pyridine ring is connected to the amino nitrogen at the 2 or 4 position of the pyridine ring. and wherein:
R.sub.1 is a hydrogen, substituted or unsubstituted alkyl, alkenyl, heterocyclylalkyl, or aralkyl, PA1 R.sub.3 is a 5- or 6-membered heterocyclic thio methyl substituent selected from groups of the formula: ##STR4## wherein M.sup.+ is an alkali or alkaline earth metallic cation such as Na.sup.+ and K.sup.+, and PA1 X is S or O. PA1 X is S or O; and PA1 Z is an anion selected from halide. PA1 R.sub.1 is selected from H, substituted and unsubstituted alkyl having 1-10 carbon atoms, alkenyl having 2-10 carbon atoms, phenylalkyl, phenyl alkenyl having 7-12 carbon atoms, PA1 X.degree. is a leaving group including halogen, preferably fluorine, also OCH.sub.3, SCH.sub.3, OSO.sub.2 OCH.sub.3, OSO.sub.2 OCF.sub.3.
The compounds of the present invention are most conveniently isolated as the zwitterionic species described by Formula I hereinabove. This structure is the principal one, however other forms can be preferred using alternate isolation procedures. Isolation from acidic solution provides salts which may be represented by the following structure: ##STR5## wherein R.sub.1, R.sub.3 and X are as defined above, and the pyridine ring is connected to the amino nitrogen at the 2 or 4 position and wherein Y is a pharmaceutically acceptable anion such as chloride, sulfate, acetate, propionate, citrate, tartrate or the like.
Isolation from basic solution (aqueous for example) yields salts which may be represented by the following structures: ##STR6## when R.sub.1, R.sub.3 and X are as defined above and M.sup.+ is an alkali or alkaline metal ion.
This invention also relates to the process of preparing such compounds of formula I, to pharmaceutical compositions comprising such compounds and to methods of treatment comprising administering such compounds to human or animal patients suffering from infection in which an antibiotic effect is needed.
There is a continuing need for new antibiotics. In particular, there is a need for cephalosporin type antibiotics which have the similar antibacterial spectrum but which have a longer lasting effect when a therapeutic dose is administered. Many of the cephalosporin antibiotics are known to be eliminated relatively rapidly from the bloodstream following adminstration, thus requiring frequent administration of medication to maintain an effective blood level of antibiotic.
Thus, it is an object of the present invention to provide a novel class of antibiotics which are useful in animal and human therapy and in inanimate systems. These antibiotics are active against a broad range of pathogens which representatively include both gram-positive bacteria such as S. aureus, Strep. pyogenes, and B. subtilis, and gram-negative bacteria such as E. coli, Pseudomonas, Proteus marganii, Serratia, and Klebsiella. Further objects of this invention are to provide chemical processes for the preparation of such antibiotics and their non-toxic pharmaceutically acceptable salts and esters; pharmaceutical compositions comprising such antibiotics; and to provide methods of treatment comprising administering such antibiotics and compositions when an antibiotic effect is indicated. It is a still further object to provide cephalosporin analogs which are retained for longer periods of time in the patient being treated than is ordinarily true of presently known cephalosporins.